delta8(9)14-androstadienes and method of preparing the same



Patented Aug. 12, 1952 PREPARING THESAME j Seymour Bernstein, PearliBiven; :JY: and Dominic J. Giancola, Jersey City; N.-J.,. assignms to American Cyana-mid .Company; New

York, N.- Y.,ea corporationof lvlaine I w g g-mng ApplicationMarcl1"22,1951, E Se'rial No. 217-;082 I This invention" re1ates- -to =new c'hemicalicompounds. More particularly; it relates-toil 1 androstadienes and methods of preparingLLthe same.

The phenomenal success reported by Kendall and others in the use of certain hormones in the treatment of arthritis and related diseases has greatly increasedthegeneral interest in the steroid field. One of the compounds found to be highly active is cortisone which occurs naturally in the adrenal cortex. Cortisone is usually described chemically as A -3,11,20- triketo-l'la, 21-dihydroxy pregnene. Other compounds *structurally-{ related to cortisone' have --beenreported I to have cortisone-like activity. and to be useful in the treatment (Sf-pathological conditions broadly classified as rheumatic diseases. This product has also been found useful in the treatment of severe burns.

We have found that certain substituted A -androstadienes may be useful in preparing physiologically active-compounds. The com-- pounds of the present invention can be prepared by a process which may beigraphically illustrated as follows:

I CH3 in which R and R are members of the group consisting of hydrogen, benzoyl and lower alkyl carbonyl radicals.

These compounds are crystalline with moderately high melting points and are soluble in the usual organic solvents. They can be recrystallized from solvents such as lower aliphatic alcohols.

The compounds of the present invention are prepared by reacting a 3,17-disubstituted- A -androstene with monoperphthalic acid or 1 per'benzoictzzacid insthe. presenceo? a-solvent.

The.=..s0lvents foun d.-.useful.t'in this' step of the ;pro.cess'are.those such. as .d'imethyleth'er, diethyl ether, .cliisopropyl ether and the like. Theprod- .uctiobtained is the 8:14 oxido derivative which son treatment with. acidified alcohols :gives. the 1: .doubly. Lunsaturated A l-iandrostadiene;

.1 Thexintermediates'. useful: in the :process -'of the :present. invention. are," in= :general, new compounds. ii A- .meth'od :"of preparing these cOmti pounds is" described in a cop'endingapplication iofiBernstein, Serial No..'168,'164, filed. June l l,

1950; now. Patent No. -.2,588,608. 'A' method 30f preparing these intermediates from known starting materials is also described in the examples hereinafter. t a I The preferred intermediate in carrying out the process-of thepresent invention is the A androstene-Bfi, 1'7e-diol diacetate. Other-intermediates can be. used in which R and R of the general formulamay be hydrogen, propionyl, butyryl, benzoyl, and the like.

The process for the oxidation step in the present invention maybe carried out at a temperature within the range of about 30C. to about 60 C. The preferredztemperature is usually the boiling point of the particular/solvent used since the reaction is preferably carried out under refluxing conditions. In the acidification the tem- 'perature'is preferablyf'from "about C'fto The compounds of the presentinventi'on: are useful in the field of pharmaceuticals and'imay serve as intermediates in the preparation;ofcom- I pounds having cortisone-like.factivity.

The'invention will be1describedfinjgreater detail in the following example'whereinrepresentative compounds within the scope of the general reaction are prepared.

Example To 11.96 mghofplatinum-oxide catalyst in 5 ml. of glacial acetic acid previously reduced with hydrogen is added 73.77 mg.;of A -androstadiene-3B,17;3-diol diacetate as prepared by Butenandt et al., Ber. 71'; 1316 (1938). The hydrogenation is carried out to constant reading.

I After one-half hour 4.54 ml. (standard temperature and pressure) of hydrogen is consumed and after 1% hours, 4.62 ml. (S. T. P.) of hydrogen. The calculated hydrogen for one double bond is 4.53 ml. (S. T. P.). The catalyst is removed by filtration. Water is added, and the resulting precipitate is collected after standing. It is Washed with a copious amount of water and has a melting point of 134-136 C. Recrystallization ml. of acetic anhydride.

formula:

to constant melting point from dilute methanol gives 52 mg. of analytically pure A -androstene-3p,17,6-diol diacetate having a melting point of 1365-138 C.

One hundred and fifty milligrams of A androstene-3;9,17B-diol diacetate in 15 m1. of dried absolute ether was treated with 0.146 g. of monoperphthalic acid (2.3 ml. of stock ether solution which contained 0.0635 g. of peracid per ml.) The mixture was refluxed on the steam bath for 6.5 hours. The ether was removed under reduced pressure; the residue was digestedwith anhydrous chloroform and -the solid (phthalic acid) was removed by filtration. The chloroform was removed under reduced pressure and the residue A -androstene-3fi,17e-diol diacetate oxide was recrystallized from dilute, acetone, and dilute methanol, melting point 187-l88 C.

Three hundred and thirty milligrams of A -androstene-3;8,17;3-diol diacetate oxide in 20 ml. of alcohol was heated to reflux when a small amount of dilute sulfuric acid was added dropwise. The mixture washeated on the steam bath for 15 minutes.

Addition of water gave an oily product which was worked up in ether in the usual manner. Removal of the ether gave an oil which was refluxed one-half hour with 5 The diacetate was worked up in ether in the usual manner. Evaporation of the ether gave'a residue which on recrystallization from dilute methanol gave pure A -androstadiene-3p,1'7fi-diol diacetate, melting point 106-108.2 (3., weight 0.18 g.,

wer 45mg, E245=18700 We claim:

' 1. Compounds of the grouphaving the general 1i I in which R and R are'members of the group consisting of hydrogen, benzoyl and a lower alkyl carbonyl radical.

2. A 3,1'l-di-(lower alkyl carbonyloxy) -'A androstadiene.

3. A -androstadiene-3B,llp-diol vdiacetate.

4. A method of preparing compoundshaving;

the general formula: V g

'- cm CH3 9 in which R and R are members of the group consisting of hydrogen, benzoyl and lower alkyl carbonyl radicals which comprises reacting a compound having the formula MQJ a in which R and R are as defined above with a member of the group consisting of monoperphthalic acid and perbenzoic acid in a solvent, recovering the reaction product therefrom and subsequently treating said product with a lower aliphatic alcohol containing a mineral acid and recovering said compound therefrom.

- 5. A- method of preparing compounds having the formula:

in which R and R are loweralkyl carbonyl radicals which comprises reacting a compound having the formula:

CH: R,

No references cited. 

1. COMPOUNDS OF THE GROUP HAVING THE GENERAL FORMULA 